The present invention relates to an improved method for treating anxious and/or depressed patients. Concurrent administration of certain azapirones with a 5-HT1A autosomal receptor antagonist provides faster onset of anxiolytic and antidepressant actions. By administering the azapirone in such a manner that formation of the 1-(2-pyrimidinyl)piperazine metabolite (1-PP) is minimized, a more robust therapeutic effect is achieved.
Certain azapirqne compounds and their pharmaceutically acceptable salts have been described as being useful in treating anxiety and depression disorders. These compounds have general structure (I) and are identified below.
(I) ##STR1## Compound Z Reference buspirone ##STR2## U.S. Pat. No. 3,717,634 gepirone ##STR3## U.S. Pat. No. 4,423,049 ipsapirone ##STR4## EP 129,128 tandospirone ##STR5## U.S. Pat. No. 4,507,303 zalospirone ##STR6## J. Med. Chem., 1988, 31:1382-1392
These particular azapirones containing the pyrimidinylpiperazine moiety as an integral part of their molecular structure give rise to 1-(2-pyrimidinyl)piperazine (1-PP) as their major metabolite. This metabolite is seen in greatest abundance following oral administration. The most studied and well-known member of this compound class is buspirone, an important antianxiety agent first approved for use in anxious patients in 1986. Although buspirone has been disclosed as having antidepressant properties by Robinson, et al., J. Clin. Psychopharmacol. , 1990, 10:675-765; it has not been generally considered to be as efficacious as classical antidepressant agents.
However, Blier, et al. in Neuropsychopharmacol. , 1997, 16:333-338; reported that buspirone exhibited both an efficacy and onset of action that was superior to classical antidepressants when the buspirone was combined with the 5-HT1A autosomal receptor blocker, pindolol. Both agents were administered separately by the oral route to a group of depressed patients in the study described by Blier.